1. Field of the Invention
The present invention relates to: a readthrough inducing agent for inducing readthrough of a premature stop codon generated due to nonsense mutations; and a drug for treating a genetic disease caused by nonsense mutations.
2. Description of the Related Art
In the genetic disease caused by nonsense mutations, protein expression is inhibited due to the premature stop codon generated by a point mutation on a gene. Examples of the genetic disease caused by nonsense mutations include muscular dystrophy, multiple sclerosis, infantile neuronal ceroid lipofuscinosis, Alzheimer's disease, Tay-Sachs disease, neural tissue degeneration, Parkinson's disease, chronic rheumatoid arthritis, graft versus host disease, arthritis, hemophilia, von Willebrand disease, ataxia-telangiectasia, thalassemia, nephrolithiasis, osteogenesis imperfecta, cirrhosis, neurofibroma, bullous disease, lysosomal storage disease, Hurler's disease, familial cholesterolemia, cerebellar ataxia, tuberous sclerosis, familial erythrocytosis, immune deficiency, kidney disease, lung disease, cystic fibrosis, familial hypercholesterolemia, pigmentary retinopathy, amyloidosis, atherosclerosis, gigantism, dwarfism, hypothyroidism, hyperthyroidism, aging, obesity, diabetes mellitus, Niemann-Pick disease, Marfan syndrome, and cancer.
For example, Duchenne muscular dystrophy arises from the lack of dystrophin protein in sarcolemma. In this disease, a stop codon is generated (premature stop codon) due to the mutation on the muscular dystrophy gene located on X chromosome, and translation is interrupted or terminated at the mutation site. Thus, normal expression of dystrophin and dystrophin-associated proteins is inhibited and as a result, patients who suffer from this disease lack dystrophin proteins.
For treating such genetic disease caused by nonsense mutations, a method employing a compound having readthrough activity has been attempted. The readthrough activity means that when a specific compound is administered to patients who have a premature stop codon generated by nonsense mutations and lack a specific protein, the above-mentioned compound acts on a ribosome and the ribosome reads through the stop codon and continues translation. As a result of readthrough, wild-type normal proteins are synthesized.
An aminoglycoside antibiotic, gentamicin and a dipeptide antibiotic, negamycin are known exemplary compounds having such readthrough activity.
Regarding gentamicin, Politano et al. has found that administration of gentamicin to patients with Duchenne muscular dystrophy led to the accumulation of dystrophin protein (see, for example, Acta. Myol. 2003, Vol. 22, pp. 15-21). In addition, it is reported that topical administration of gentamicin to the respiratory epithelium of patients with cystic fibrosis can correct typical electrophysiological abnormalities (see, for example, N. Engl. J. Med. 2003, Vol. 349, pp. 1433-1441). Furthermore, clinical trials of gentamicin have been conducted in the United States as a therapy for genetic diseases. However, there is concern for high toxicity of gentamicin. Since long-term administration is required, gentamicin is not a satisfactory therapeutic agent for the patients of genetic disease caused by nonsense mutations.
Regarding negamycin, it is confirmed that administration of the compound to muscular dystrophy model mice restores dystrophin expression (see, for example, International Publication No. WO 2002/102361). However, negamycin is an unapproved drug. There is an immediate need for a drug against genetic diseases caused by nonsense mutations. Thus, negamycin is not realistic as a therapeutic drug for genetic diseases caused by nonsense mutations.
In addition, clinical trial of ataluren (PTC124), which has readthrough activity, has been conducted in the United States as a drug for, for example, Duchenne muscular dystrophy. However, the trial is stopped at phase III at present. As mentioned above, a drug against genetic diseases caused by nonsense mutations is needed immediately. Thus, ataluren is not realistic as a therapeutic drug for genetic diseases caused by nonsense mutations.
In view of the above, demand has arisen for prompt development of a readthrough inducing agent that contains a compound having low toxicity and readthrough activity and of a drug for treating a genetic disease caused by nonsense mutations.